The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
All publications and applications referred to herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
K-Ras (or Ki-Ras or Kirsten-Ras or KRAS) is a 21 kD member of the Ras family of GTPase proteins and a necessary component in cell signaling. Activated K-Ras typically activates downstream kinases necessary for the propagation of growth factor and other receptors signals (e.g., c-Raf and PI3-kinase). Unfortunately, genetic alterations in the gene encoding K-Ras are associated with development of neoplasias, and the mechanism of activation is relatively well understood.
Cancer-associated mutant K-Ras is constitutively active, with prolonged stabilization of its GTP-bound (active) state, and is thus able to constitutively activate downstream effectors such as Raf kinase and phosphoinositide-3 kinase (PI3K). Both of these kinases play important roles in proliferation/survival/anti-apoptotic signaling pathways. These mutations have been implicated in insensitivity to EGFR-targeted anti-cancer therapies as mutations in K-Ras predispose cancer cells to be significantly less responsive to EGFR targeting therapies (e.g., Panitumumab, Cetuximab, etc.). Interaction with the Ras GTPase activating protein (RasGAP) is vital to the timely inactivation of K-Ras, resulting in more efficient hydrolysis of GTP to GDP. The conformational changes in K-Ras structure due to the GTP hydrolysis result in the elimination of K-Ras' affinity for effector proteins, thereby inactivating downstream proliferation and anti-death pathways. Cancer-associated mutations in K-Ras have been shown to interact poorly with RasGAP, therefore remaining in the “on” or constitutively active state.
Approximately 33% of all human tumors express mutant Ras, and these mutations often stabilize Ras in GTP-bound (active) state. Mutations found in K-Ras associate strongly with pancreatic cancer (90%), biliary tract cancer (33%), colorectal cancer (32%), and lung cancer (20%), among others. Approximately 20-25% of all human tumors harbor an activating mutation in gene encoding K-Ras.
Examples of cancer-associated mutations are found at glycine-12 (Gly12), Gly13, and glutamine-61 (Gln61), with Gly12 being the predominant site of mutagenesis (88%). Most notably, while the most common Gly12 mutations are defects in the same position, different mutations have their own different characteristics. For example, expression of G12C is often associated with a reduced response to cisplatin and an increased sensitivity to taxol and pemetrexed, whereas the expression of G12D mutant typically results in resistance to taxol treatment and sensitivity to sorafenib. The G12V mutant shows a strong sensitivity to cisplatin when compared with the wild type variant and is slightly more resistant to pemetrexed. Such diversity in treatment response is compounding difficulties in finding adequate treatment with drugs that are specific to K-Ras, and also highlight that specific mutant forms of K-Ras may require specific drugs for inhibition of the K-Ras activity.
More recently, specific drugs have been proposed to target a particular mutant form of K-Ras. For example, WO2013/155223A1 discloses small molecule inhibitors for G12C mutant forms. While promising, issues with restricted use and potential toxicity may limit compounds presented in the '223 reference. To circumvent mutant specific forms, allosteric inhibitors were proposed (PLOS One October 2011, Volume 6, Issue 10, e25711). However, that report did not distinguish among different mutant forms.
In view of the important role mutant K-Ras plays in various neoplastic disease states, it would be advantageous to be able to identify compounds that bind specifically to the mutant K-Ras protein forms associated with cancer diseases states and/or specific mutant forms, and most preferably to a specific mutant type with little or no binding to the wild type.
Thus, even though various forms of inhibitors for K-Ras are known in the art, there remains a need for compositions and methods that preferentially or even selectively target mutant K-Ras, and especially a single mutant form.